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Covid-19 Antibody Update for April 8

Let’s do an update on the antibody situation in this epidemic (a bit of antibody/immunology background here if you would like some). The word is today that the CDC is starting several efforts to do antibody testing. One of these is to look at people (from areas that showed widespread cases of coronavirus) who never showed any symptoms themselves. How many of these folks will turn out to have had asymptomatic cases anyway?

The second study is more wide-ranging across the US population – similar efforts are underway from others (here’s one being run out of Stanford, and there’s an interesting round of testing around Telluride, Colorado), and combining these will help to give us a picture that at the moment we just don’t have: knowing the actual prevalence rate of the disease is vital for figuring out our strategy in the coming months. The third CDC study is specifically looking at health care workers, a population that sadly has had every chance possible to be exposed to the virus, to see how many of them show exposure compared to the never-had-symptoms group and the general population.

A note about antibody testing is in order, and it’s the usual concern about diagnostic tests in general. The mathematics mean that the higher the prevalence of what you’re testing for in your population of subjects, the better the accuracy of the results. So if your disease has a low prevalence, your test has to have very low false negative and false positive rates to be meaningful or even useful at all. Here are a couple of blog posts that run through the numbers as illustrations of this, and here is a good Twitter thread on one of the tests (Cellex) that the FDA has recently given Emergency Use Authorization for. That one has a 93.8% sensitivity and a 95.6% specificity, which means that if (for example) 4.5% of the US population has had the virus, that a positive result with that test only means a 50% chance that you actually are positive. If 30% of the population has actually been infected, the test is right 90% of the time, and so on (see the link for details). I don’t know what tests the CDC and Stanford surveys are using and what their specificity/selectivity numbers are, although we can be sure that they know all about the statistics. But everyone else should, too.

One of the uses of antibodies from recovered patients, naturally, is “convalescent plasma” treatment. If someone has raised neutralizing antibodies to the coronavirus, their blood plasma can be given to someone else as an emergency measure, and those antibodies should work on them as well. This has already been used on a small scale (it’s an old technique), but unfortunately it’s not easy to scale up. Depending on the antibody titer of the recovered patient, it may be that one person might have enough antibodies to treat only one other person, and this is naturally a relatively labor-intensive process which will be reserved for the critically ill. Another thing to remember is that these antibodies are effective on infusion, but that you’re not giving the recipient their own lasting antibody response by doing so – their immune system will have to mount that.

But how many people have raised neutralizing antibodies? That’s another key piece of data that we don’t really know yet. This new report from Fudan is worth thinking about, where they’ve analyzed 175 patients discharged from hospitals in Shanghai after coronavirus infection. Neutralizing antibodies appear about 10 to 15 days after the onset of disease (which sounds about right) and target three different regions of the “spike” protein on the virus. (Interestingly, these do not cross-react with the earlier SARS coronavirus spike protein). The total amount in the blood (the titer) varied quite a bit between individuals – notably, younger patients had far lower levels than older ones did, which raises the question of how immune they really are. In fact, ten of those young patients had no detectable neutralizing antibodies at all (!) and overall, about 30% of the entire cohort failed to develop a high antibody titer (although they had similar disease progression before their recovery).

This presumably means that other parts of the immune system played a greater role in clearing the virus, which is fine – except that those long-lasting antibodies and memory B cells are the key to staying immune. A lot of people are (understandably) talking about having some sort of “immunological passport” system to clear people for work, etc. before we are able to vaccinate the population, and these results may be telling us that that will be a complicated process, one that might not clear as many people as one would hope.

We’ll see if the CDC numbers and others back up these results in our own populations. Stay tuned – the antibody story is a big part of all this, and it’s just going to get bigger.

Update: forgot to mention this paper. Thanks to a collaboration between Scripps and the University of Hong Kong, we now have an X-ray crystal structure of a neutralizing antibody bound to the receptor-binding domain of the coronavirus spike protein. That’s one of those three regions mentioned above that such antibodies have been found to interact with. For those into structural biology, there are interesting insights into conserved protein epitopes, and some good points about how such antibodies may be more more relevant in vivo than they appear to be in some in vitro assays.

37 comments on “Covid-19 Antibody Update for April 8”

  1. Tim says:

    “expect that those long-lasting antibodies and memory B cells are the key to staying immune”

    Should that be “except”?

    1. Derek Lowe says:

      That it should – my brain does that one every so often while connecting with my fingers. Fixed.

  2. Toni says:

    Apropos antibody testing regarding sensitivity and specificity:
    But what if you take a second test?
    If this is also positive, the probability that it is still a false positive is significantly reduced, because the ratio of right-positives to false-positives has shifted in favour of the former.
    This is actually strange, since the second test is as exact as the first, but this now meets a higher prevalence of test-positives, because the many test negatives from the first test have been omitted and thus the ratio has clearly shifted positive and negative aspects. This makes the second test more accurate.

    1. Dan says:

      Assuming the probability of failure on the two tests is independent. (I don’t know if that’s true or not.)

      1. toni says:

        Of course, I think it will possibly depend on whether the error rate is due to some technical issues or whether there is intrinsic reractivity (cross reactivity etc.).

      2. mayfin says:

        Indeed, only if the tests are independent. But from first principles I’d have thought that there are good reasons to suspect that false positives due to a lack of specificity WON’T be independent – if there was something else in the patient’s sample other than SARS-COV-2 that the test reacted to first time round, there’s no reason (other than, ironically, a lack of sensitivity in general) that the test won’t react to it again second time round,

  3. Ogamol says:

    This, plus an article I read weks/months ago about relative endurance of youth to athletes, suggests youthful immune systems may have a different level of robustness in different stages of response. Emphasis on “may” and “different”, because of the inconsistency. (The cytokine storm sequences described at!po=3.26633 also color my input.)

    1. Patrice Milos says:

      Very disappointing indeed…just demonstrates how challenging it is to bring everything together even with a population size of ~8,000 people.

  4. Paul says:

    So if we know the molecular structure of these antibodies, can we develop a monoclonal antibody from that and use that in critically ill patients? It seems like it would be quicker to get to widespread trials than a vaccine.

      1. Jordan says:

        Would using monoclonal antibody treatment be expected to slow the development of humoral immunity? Or would there be enough immunogenic epitomes floating around on the viral particles to negate the effect of the infused antibodies occupying target sites on the spikes in developing native immunity?

  5. Bill says:

    I think these antibody tests still have a very valuable use at very low (or very high) disease prevalence– while at low prevalence a positive is likely a false positive (and of course at high prevalence a negative is likely a false negative) and thus not so useful for telling someone they have had the disease, if you know the sens/spec of the test (and those #’s are also valid in the population in which you are testing) you can work backward and determine the true disease prevalence from the # of positive and negative results.
    Right now that is a very important thing to know, and much debated, due to incomplete testing and unknown % of asymptomatic cases.
    For example, with the sens/spec you listed, per 100 tests:if zero prevalence you will get of course 4.4 positive results (all false) and 95.6 negativesat 5% you get 8.9 positive (about half false) and 91.1 negative (almost all true).10% gives 13.3 positive (70% true) and 86.7 negative (99.3% true)

  6. Brian R says:

    Thanks Derek, for the update and for the link to the Furan report. I hadn’t seen it yet. But I’m VERY sceptical of the notion that the asymptomatic, but with positive virus tests, will have SARS Cov2 antibodies at all. They may show some PCR’able SARS-Cov-2 in a swab, but that they haven’t had any inflammation, even fever, means there immune response didn’t need to/didn’t get stimulate to get ramped up.

    This latter is an after the fact supposition. The initial rationale for me, which your Furan paper supports though far from proves, was a MERS paper I came across recently showing that healthcare workers, in close contact with multiple patients, that were asympotamatic but did show early detectable virus levels, did NOT show antibodies upon followup some months later, in contrast to patients who WERE symptomatic. And similar as you stated here for SARS Cov2, with both MERS and SARS, the antibody levels several months after recovery were pretty nicely correlated with the severity of the illness. i.e. the sicker you were, the more antibodies you eventually make. Which makes sense evolutionarily, bugs that make us real sick should hopefully be the things the immune system remembers for a long time. But also, it also makes sense that the higher your levels of virus are, for longer periods of time, you should get more T cell activation and B cell activation (over time) and more likelihood that you are going to wind up with B cells with decent antibodies.

    At any rate, I think the notion that the ability to do serology tests is going to be a game changer, and maybe allow us to put an end to social distancing earlier, which I’ve seen bandied about on some websites articles, well, I wish I was more hopeful about it…

    1. Barry says:

      or, equally, it could be that most of the symptoms are driven by your immune response, and patients who don’t mount an immune response won’t manifest fever etc.

    2. Sharon says:

      Well, you can get immunized by a vaccine of a “weakened virus” with no side-effects right?
      So, why should it be different with the “real virus” infection?

      1. Brian R says:

        good point. I will be happy to be wrong about this. But there are differences in that vaccines are usually co-administered with an adjuvant, which locally stimulates the immune response (I am NOT an immunologist, but I’ve had to self-educate on multiple projects which interfaced with antibody techniques). Also, aside from the flu shot (which has it’s issues, part of which is the moving target but another part of which is individual differences), most effective vaccines are designed to have multiple “boost” injections. Those additional boosts allow for the maturation of the immune response as much as additional stimulation. The antibody genes in the B cells hypermutate, to achieve antibodies with the affinity and avidity to specific epitopes, and hopefully also a subset develop into memory cells. The initial response stimulates the presentation of epitopes that the B cells start to recognize, but the optimal antibody gene has not necessarily been reached. And if antibodies with sufficient affinity HAVE been acheived after a single injection, it will be in only a very small population of B cells. The additional boosts allow for propagation of the B cells with effective antibodies.

        But as other commentators have mentioned, there may be another reason that the virus is being cleared that is NOT dependent on the development of antibodies. Based on my screens of the literature, there is a good chance the T cells are clearing it pretty well in a subset of people, when they are exposed to low doses.

        But I could be wrong, the CDC screens that are starting will be able to get a read on whether there are people with asympotamatic virus presentation develop antibodies that are relatively longlived .But note, with both SARS and MERS, so far those who have long lived antibody levels largely originally presented with severe symptoms. Not enough studies were published in either case that makes me 100% convinced, but no studies I have seen yet make me think that the asymptomatic will have antibodies.
        Small n study, but still:
        Alshukairi, A. N., et al. (2016). “Antibody Response and Disease Severity in Healthcare Worker MERS Survivors.” Emerging infectious diseases 22(6): 1113-1115.

  7. Barry says:

    “younger patients had far lower levels than older ones did”

    This suggests:
    1-these Abs are not what clears the infection in young patients
    2-these Abs may be players in the cytokine storm that kills older patients but not younger ones

  8. Scott T Stewart says:

    What is the gold standard that they are measuring these antibody tests against to get sensitivity and specificity numbers?

  9. Anonymous says:

    Current tests are not doing so great according to the University of Oxford:

  10. eub says:

    Do we have much understanding of why the immune response to the “common cold” coronaviruses does not prevent re-infection with the same viral strain? Is SARS-CoV-2 going to be different, and why?

  11. Marko says:

    ” Update: forgot to mention this paper……some good points about how such antibodies may be more more relevant in vivo than they appear to be in some in vitro assays. ”


    This paper shows some encouraging results using CP , and found that 39 of 40 plasma donors had neutralizing titers > 1:160 , although they chose the plasma from higher-titer donors for the study ( >1:640 ) :

  12. Alan Goldhammer says:

    I read the pre-prints every morning and here is one that caught my eye: They honed in on a very potent neutralizing antibody. I’ve seen a couple other similar papers and we know that Regeneron have a R&D program going on in this area. mAb scale up production is straight forward.

    I’m still dismayed that we don’t have a good validated serology test that can be broadly deployed. It’s the only way we can get a reasonable estimate of the background level of infection.

    1. Marko says:

      Here’s what caught my eye in that preprint :

      “Antibody cocktails including S309 along with other antibodies identified here further
      enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants….”

      So , a mix of Abs seems the way to go. Polyclonal , not monoclonal. Kinda the way our own immune system works.

      Hmmm , maybe convalescent plasma is worth a shot. Of course , nobody would make $zillions in the stock market if we go that route. Never mind.

  13. bacillus says:

    There could also be a large cohort whose innate immune system cleared the virus before any adaptive immune response could develop.

  14. Michael says:

    This is extremely interesting, “ten of those young patients had no detectable neutralizing antibodies at all (!)”. Could this be because younger individuals are far more capable of clearing the SARS-CoV-2 virus via their innate immune system (NK cells, etc.) and at such a rapid pace that their adaptive immune response wasn’t mobilized? Also, if this were the case then it stands to reason their bodies wouldn’t have had enough time for their adaptive immune system to develop detectable neutralizing antibodies.

    1. Derek Lowe says:

      That’s definitely a hypothesis that has been advanced for this.

  15. Rich Stern says:

    I think Barry’s comments are right on the money. Perhaps the innate immune response (TLRs and such) is very important during initial infection and for whatever reasons, young people have a better innate immune response. Thus they do not develop a robust adaptive immune response. Older people, having a lesser innate response, develop a stronger adaptive response that causes more significant symptoms, which lead to higher mortality. All speculation, I know. But years ago I conducted research on poxviruses. I once infected (instilled intranasally) mice with VERY large amounts of virus, so they developed severe lungs infections. Some were then treated with corticosteroids, others were not. All the mice got very sick, but the ones that did not receive steroids died. Almost all the ones receiving steroids survived. The point of the study was not related to whether or not steroids helped with survival per se, But it was pretty clear that an overly robust immune response resulted in higher mortality. Based on the timelines of the study, the immune response would have been an adaptive immune response, although data was not collected in this regard. I think about this result often. And it has made me think that if I end up in the hospital with COVID, please infuse me with steroids.

    1. Beck says:

      I think you are right. I had Covid and I am 32 and after 25 days of no improvement I was given a large dose of prednisone for 5 days. After that, the fever finally broke and breathing became easier.

    2. Beck says:

      Yet my antibody results keep coming back negative.

  16. ghyu says:

    How does IgG from plasma help? Don’t you need IgA secreted into the lungs?

  17. ferdo says:

    Innate immune system antimicrobial peptides like cathelicidin and defensins are vitamin D depended. (

    Victims of COVID-19 are likely vitamin D deficient: obesitas and diabetes are symptoms of vitamin D deficiency. Age and dark skin color are risk factors of it.

    So take your 5000 IE vitamin D3 per day and you are protected!

  18. matthew49 says:

    Why not inoculate horses and use the immune serum from the horses, like 100 years ago? I believe there are still some herds maintained and used to make antibodies for research purposes.

    1. Gd says:

      Risk of severe allergic reactions I guess.

  19. Gd says:

    A first larger population sample was tested in the German hotspot of Heinsberg, both for virus and antibody presence. Preliminary data suggest that 15% of the town were infected, 2% with an active infection. The study triggered strong interest from the news media but expert opinions were lukewarm due to the small sample size, unclear rate of false positive results, and media hype.

    Link to the report:

  20. Dr Devang says:

    Is there any correlation between the titer of convalescent plasma and a load of immunoglobulin given to the patients?
    I mean when we say a 200 ml of plasma with SARS-CoV-2 antibody tier >1:320 was given, what a load of hyperimmune immunoglobulins (in IU or ml) would have been given to the patient?

    thanking you in anticipation.

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